Apixaban is chemically known as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl) phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and represented by following structural Formula I,

Apixaban (BMS-562247-01) is an anticoagulant used for the prevention of venous thromboembolism and venous thromboembolic events. Apixaban is marketed under the trade name “Eliquis” and is being developed in a joint venture by Pfizer and Bristol-Myers Squibb.
U.S. Pat. No. 6,967,208 specifically discloses Apixaban and its process, which comprises reaction of 4-iodoaniline with 5-bromovaleryl chloride to give lactam intermediate, which is further dissolved in chloroform and reacted with phosphorus pentachloride, quenched with water and condensed with morpholine to give 1-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one. The obtained 1-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one is reacted with ethyl (Z)-2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate to give ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. The resulted compound undergone Ullmann Reaction with piperidin-2-one in presence of CuI, potassium carbonate at 130° C. for 24 hours to give ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate, which is subsequently amidated by ammonia solution in ethylene glycol to give Apixaban. The reaction sequence of above patent is illustrated in scheme 1.

U.S. Pat. No.6,919,451 discloses another process for the preparation of Apixaban, which comprises reaction of piperidin-2-one with phosphorus trichloride, treated with lithium carbonate and condensed with morpholine to give 3-morpholino-5,6-dihydropyridin-2(1H)-one. The obtained 3-morpholino-5,6-dihydropyridin-2(1H)-one is reacted with ethyl (Z)-2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate in the presence of base to give ethyl 1-(4-methoxyphenyl)-7a-morpholino-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate, which is further treated with trifluoroacetic acid to give ethyl 1-(4-methoxyphenyl)-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. The resulting compound was undergone Ullmann reaction with 1-(4-iodophenyl)piperidin-2-one in presence of CuI, potassium carbonate at 125° C. for 10 hours to give 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid, which is subsequently reacted with isobutyl chloroformate and ammonium hydroxide in the presence of triethylamine to give Apixaban. The reaction sequence of above patent is illustrated in scheme 2.

The main drawbacks of the above processes are the use of laborious column chromatographic purification at multiple stages, which not only increases the consumption of solvent but also difficult to handle on the commercial scale, including the obvious practical limitations of column chromatography on industrial scale. Also the present process uses Ullmann Reaction which requires harsh condition i.e. heating the reaction mixture at 125-130° C. for up to 24 hours in the presence of Copper (I) catalyst, which is difficult to operate on the large scale. Furthermore, the yield at the intermediate stage is very low (˜21%) which makes the process uneconomical and industrially unviable.
U.S. Pat. No. 7,396,932 discloses process for the preparation of Apixaban, which comprises reaction of 3-chloro-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one with ethyl (Z)-2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate in the presence of base to give ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. The nitro group of the resulting compound was reduced and reacted with 5-halovaleryl chloride wherein halogen can be selected from chloro or bromo to give ethyl 6-(4-(5-halopentanamido)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. It is further cyclized to give ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. The obtained compound was subsequently amidated by formamide in the presence of dehydrating agent to give Apixaban. The reaction sequence of above patent is illustrated in scheme 3.

CN patent No. 101967145B discloses preparation of Apixaban, which comprises reduction of 1-(4-nitrophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one with sodium sulfide to give 1-(4-aminophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one which further coupled with 5-chlorovaleryl chloride in the presence of organic base, followed by in-situ cyclization to give 3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one. The resulting compound was reacted with ethyl (Z)-2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate in the presence of alkali metal iodide as a catalyst and triethylamine, followed by treatment with aqueous HCl to give ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. The resulting compound was amidated by ammonia/water to give Apixaban. The main drawback of the process is the use of sodium sulfide and alkali metal catalyst which is hazardous and makes the process environmental unfriendly. The reaction sequence of above patent is illustrated in scheme 4.

The processes disclosed in the above mentioned prior art(s) are having several limitations like multiple chemical steps, overall low yields, use of column chromatography, use of expensive and toxic reagents etc.
Thus, there is a need to develop a simple, economically viable, industrially feasible and environmental friendly process for the preparation of Apixaban, which overcomes the drawback of the above mentioned prior arts.